Innate immunity plays a critical role in the body's defense against prokaryotic and eukaryotic pathogens such as viruses, bacteria, fungii, parasites etc. Indeed, acute and chronic infections caused by viruses constitute a major worldwide public health crisis with significant unmet medical need (1,2). In addition to infectious diseases, viruses cause 15-20% of all cancers worldwide including liver, cervical, and pancreatic cancers, each resulting in significant mortalities and morbidities.
In addition to human suffering, viral diseases result in overwhelming healthcare costs and loss of productivity. For example, worldwide 500 to 600 million people are chronically infected with HBV and HCV, and 1 to 2 million deaths occurs every year due to virus-induced liver cirrhosis and liver cancer. Tens of thousands of patients worldwide are in desperate need of liver transplantation. Human papilloma virus infection leads to cervical cancer and incidence of Kaposi sarcoma associated with HIV infection is all well documented. Pandemic influenza is characterized by high levels of morbidity and mortality in humans, and associated with increased levels of infection and pathogenesis due to the lack of pre-existing immunities against its novel antigenic subtype. Antivirals may not only potentially slow the spread of pandemic influenza, but may ultimately be a solution. Tuberculosis caused by Mycobacterium tuberculosis (Mtb) kills more people today than any other bacterial infection. Nearly a third of human population, in over 90 countries, is infected with Mtb and 2 million people die each year from the disease.
Although vaccines are available as prophylactic against a limited number of viruses, they have no real therapeutic benefit for those already infected. Moreover, vaccines against certain viruses (e.g., influenza vaccines) are unlikely to make a significant impact on mortality in a pandemic because of the time required to generate enough doses of a suitable vaccine against the new human strain after it has been identified. Use of adjuvants can augment the potency of vaccines and afford protection against broad range of viruses.
Consequently, our antiviral defense almost exclusively relies on the use of antiviral drugs. Unfortunately, many medically important viruses, particularly RNA viruses are dangerous, cannot be tested in model systems, or cannot be propagated for testing of potential candidate drugs.
Many of the current antiviral drugs have been developed as viral polymerase, protease, integrase, and entry inhibitors. However, drugs designed to inhibit viral growth can also adversely affect host cells since viral life cycle engages normal host cellular functions. The limited viral targets that are amenable to antiviral intervention further compound antiviral drug discovery. Consequently, despite almost 50 years of antiviral research, our arsenal of antiviral drugs remain dangerously small with only about 34 antiviral drugs in the world market, mostly against HIV and Herpes viruses.
Further, the current treatment options for several chronic viral diseases including HCV and HBV remain extremely limited and challenging. Indeed, viral rebound upon cessation of therapy, drug-induced toxicity, and emergence of resistant strains under selective pressure of antiviral drugs continue to remain serious problems in current antiviral therapy. Complete eradication of the virus is rarely achieved, and at best in a very small cohort of patients, because current antiviral therapy produces inadequate and unsustainable antiviral response. The developments of drugs that target host-encoded functions provide an alternate strategy for antimicrobial discovery.
Viruses have also continuously evolved clever strategies to evade host immune response and to develop resistance to drugs through a variety of mechanisms. Cells protect themselves from microbial infections via the cellular sensors including Retinoic acid inducible gene (RIG-I) and other RIG-like proteins (RLRs), MDA5, nucleotide oligomerization domain protein-2 (NOD2 and other Nod-like proteins (NLRs). Activation of these proteins via the interaction of pathogen recognition receptors with the microbial nucleic acid or peptides cause the Interferon signaling pathway resulting in IFN production that protects cells from infections. Indeed, it is being recognized that both DNA and RNA viruses inhibit type I Interferon (IFN) production thereby suggesting that controlling the IFN response is essential for the survival of a broad range of viruses (3,4). Thus, the development of effective antiviral therapies must involve the use of combinations of new classes of drugs each with novel, multiple mechanisms of action including those that stimulate host immune response for eradication of the virus. Similarly, bacteria have evolved unique mechanisms that result in resistance to antibacterial agents. Thus, the development of effective antibacterial therapies must involve the use of combinations of new classes of drugs each with novel, multiple mechanisms of action including those that stimulate host immune response for eradication of the bacteria. Many different types of cancers have evolved different mechanisms to develop resistance to anticancer agents. Thus, the development of effective anti-cancer therapies must involve the use of combinations of new classes of drugs each with novel, multiple mechanisms of action including those that stimulate host immune response for eradication of cancer.